Topical amlodipine salts for the treatment of anorectal diseases

ABSTRACT

Provided is a topical pharmaceutical gel composition of an amlodipine salt and methods for its use in the treatment of anorectal disease.

The present disclosure relates to topical pharmaceutical gelcompositions containing amlodipine salts. Topical pharmaceutical gelcompositions containing amlodipine salts are suited for use in treatinganorectal diseases such as hemorrhoids, anal fissure (acute andchronic), painful conditions after anorectal surgery, perianal abscess,prolapsed thrombosed piles, perianal haematoma, cancer invading thesphincters (anorectal cancer), anal herpes, anal warts, anal itching,proctalgia fugax, constipation, anal bleeding and Crohn's disease oranother inflammatory bowel disease related anorectal disorders.

Anorectal disease refers to ailments of the anus and/or rectum. The mostcommon conditions include hemorrhoids, anal warts, anal fissures,anorectal abscesses and anal fistulas.

Hemorrhoids develop when tissues of the rectum and anus become swollenand inflamed. Hemorrhoids can be located inside the anus (internalhemorrhoids) or in the area surrounding the anus (external). Symptomsinclude pain, inflammation and itching.

Treatment for mild cases of hemorrhoids may include sitz baths, coolcompresses, pain relievers and over-the-counter topical medication. Forchronic hemorrhoids, there are several options such as hemorrhoidbanding, injections and infrared coagulation. Surgical options such ashemorrhoidectomy and stapling are reserved for the most serious cases.

Condyloma, or anal warts, are caused by the human papilloma virus (HPV)and form on the skin around the anus. There are many types of papillomavirus. Some types develop warts on the hands and feet while others causegenital and anal warts. Many people do not complain of any complicationsfrom anal warts. Others complain of itching, bleeding or moisture in theanal area.

Treatment for anal warts include cauterization, ointments or a specialtype of acid (podophyllin or bichloracetic acid). Several treatments arenecessary to cure anal warts. Even if the warts have been “removed,” thevirus can remain in the skin tissues. Follow-up visits are necessary forseveral months.

Anal fissures are small tears in the lining of the anus. These tears canbe caused by hard, dry bowel movements, diarrhea and inflammation.Symptoms include itching, pain and bleeding.

The anal fissure is acute when it heals with 4-8 weeks of conservativetherapy. If this therapy fails and the fissure becomes chronic (S.Schlichtemeier, A. Engel, Aust Prescr, 2016, 39, pp 14).

Overall incidence of anal fissure is of 1.1 per 1000 person-yearstranslates to an average life time risk of 7.8. Approximately 40% ofpatients develop chronic anal fissure.

The pathophysiology of anal fissures is not entirely clear andunderstood. A widely accepted scientific explanation (M. H. Madalinski,World J Gastrointest Pharmacol Ther, 2011, 2(2), pp 9; M. M. vanMeegdenburg, M. Trzpis, E Heineman, P. M. A. Broens, Medical Hypotheses,2016, 94, pp 25; M. van Outryve, Acta Chirurgica Belgica, 2006, 106(5),pp 517) is that an acute injury leads to local pain and spasm of theinternal anal sphincter. This spasm and the resulting high resting analsphincter pressure leads to reduced blood flow and ischaemia and poorhealing. Unless this cycle is broken the fissure will persist or becomechronic fissure.

Clinicians agree that a constantly elevated rest pressure in the analsphincter plays a crucial role in the pathogenesis of anal fissures.Schouten et.al. (W. R. Schouten, J. W. Briel, J. J. Auwerda, Dis ColonRectum, 1994, 37, pp 664) showed that the anodermal blood flow ratescorrelated inversely with the anal resting pressures measured by Dopplerlaser flowmetry and anorectal manometry, respectively. The increasedpressure resulted in a lowered blood flow. Patients with fissures hadhigh resting pressures and also low perfusion rates. This low perfusioncan be attributed to the scarcity of small arteriolar anastomosesbetween the end branches of the left and right inferior rectal arteriesdorsally. Fissures generate in this region, when the resting sphincterpressure is sufficiently higher than the pressure in the smallarterioles. Chronic anal fissures can therefore be considered asischemic ulcers. Moreover Maria et.al. (G. Maria, D. Brisinda, M. P.Ruggieru, et al. Surgery, 1999, 126, pp 535) demonstratedantiendothelial antibodies in patients with an anal fissure, not incontrols. These antibodies activate the endothelium, generatingvasoconstriction and procoagulant activity. This mechanism also inducesischemia of the anoderm and the formation of a fissure. The end stage ofthe fissure as an ischemic ulcer is a fibrotic lesion with a concomitanthypertrophic papilla and sentinel skin tag. Fibrosis is an importantobstacle to healing and can result in an atonic ulcer. Chronicinflammation of the fissure can also provoke a local abscess andfistulisation.

The majority of acute fissures resolve with the aid of topical localanesthetics and stool softeners. Moreover, a proportion go on to becomechronic. Whatever their cause, it is known that they are associated withan increased resting tone. Treatment for fissures has therefore beentargeted at reducing resting anal pressure, which in turn results in anincreased blood flow to the posterior commissure and healing of thefissure.

The traditional treatment to reduce tone in the anal sphincter has beenthe anal dilatation in which 4 fingers are gradually inserted into theanus under deep general anesthesia and gently separated thus breakingthe fibers of the internal sphincter in a radial fashion. The risks tocontinence of this approach are obvious and have been estimated at 30%for temporary incontinence and up to a 10% risk of permanent fecalincontinence. It has consequently fallen out of favor with mostsurgeons. The preferred procedure is the lateral internalsphincterotomy, which can be performed by either an open or closedtechnique.

Although lateral sphincterotomy has become the gold standard for thetreatment of anal fissures, these complications have driven the searchfor other methods of reducing anal pressure. Research has been directedtowards finding a means of pharmacologically reducing anal pressurewhilst leaving the ring of internal anal sphincter muscle intact.

Chemical sphincterotomy has been tried using a variety of novel agentsincluding topical GTN, calcium channel blockers such as nifedipine ordiltiazem and botulinum toxin. Some of these agents were found to beeffective in healing chronic anal fissure with negligible side effectsand are now considered as first line treatment for chronic anal fissure.

Only glyceryl trinitrate (GTN) ointment is approved for the treatment ofmoderate to severe pain associated with chronic anal fissure. In threePhase 3 studies conducted and submitted to the regulatory bodiesworldwide, healing of anal fissures in patients treated with Rectogesic4 mg/g Rectal Ointment was not statistically different from placebo(Public assessment report, UK/H/0823/001/MR). Severe headaches caused byapplication of GTN resulted in 30% of the patient to discontinuing itsuse. Various concentrations of GTN has been tested but 0.2% dosing (×2-3daily) offers the same healing rate as with higher concentrations butwith a lower incidence of headache. The best way to minimize and/oreliminate headaches is to apply the GTN on the anal area in recumbentposition. An immediate rush or heat is felt in the head caused byvasodilatation of cerebral vessels which subsides just as quickly. Thepatient then can get up and resume normal activity. Application of GTNin the anal canal is unnecessary and causes undue pain as its mode ofaction is through absorption from the skin (such as nitropaste fortreatment of angina pectoris). Application of GTN in a hurry and insitting or standing potion increases the incidence of headaches (6% v56%) and may result in premature discontinuation of treatment (A. M.Abcarian, H. Abcarian, Internal Medicine Review, 2018, 4(1), pp 1).

CCBs have been used for many years in coronary heart disease becauseblockade of the calcium channel produces smooth muscle relaxation in thearteriolar wall. Several studies suggest that topical CCBs are aseffective as GTN and have fewer side effects (K. N. Zaghiyan and P.Fleshner, Clin Colon Rectal Surg, 2011, 24, pp 22). Despite of the useof CCBs in the treatment of chronic anal fissure, approved productcontaining CCBs is available on the market. In other cases, onlycompounded creams or ointments containing CCBs can be used for thetreatment. Compounded drugs have several drawbacks, such as limitednumber of compounding pharmacies, Physicians has to write a “recipe” forthe compounded CCBs (off-label use), and concentration of compoundeddrugs is highly variable between pharmacies, prescriptions and withineach tubes and lack of reimbursement.

CCBs reduce the amount of calcium entering cells of the heart and bloodvessel walls. Calcium passes into these cells through the ion channels.These channels are blocked by CCBs, thereby reducing the amount ofcalcium entering cells of the heart and blood vessel walls. As a result,the blood vessels relax, and the heart muscle receives more oxygenatedblood, which is how CCBs are able to lower blood pressure and treatangina. Some CCBs also block calcium going into the conducting cells inthe heart and have the added effect of slowing the heart rate.

There are two distinct chemical classes of CCBs: the dihydropyridines(such as nifedipine and amlodipine) and the nondihydropyridines(diltiazem and verapamil) The two classes both help to relax and widenarteries but non-dihydropyridines have an additional effect on theheart's conduction system and can help to control certain fast heartrhythms (such as atrial fibrillation). This is becausenon-dihydropyridines also block calcium going into the conducting cellsin the heart, which has the effect of slowing down the heart rate.

Targeting the internal anal sphincter with topically applied amlodipinesalts relies on the effective transcutaneous flux of drug substance.

There is a significant and very long-standing need to identify agentswhich can be applied topically to treat anorectal diseases, and whichhave favorable benefit to risk rations. Optimally such agents shouldprimarily act locally, and systemic absorption should not result inblood levels high enough to cause significant systemic effect ortoxicity.

SUMMARY

Provided is a composition for the topical treatment of anorectaldiseases, containing a therapeutic amount of a calcium channel blocker,such as an amlodipine salt.

Also provided is a composition for the topical treatment of anorectaldiseases prepared by a method comprising dissolving or suspending acalcium channel blocker, such as an amlodipine salt, in an appropriatepreparation for topical administration. Also provided is a topicalpharmaceutical gel composition comprising an amlodipine salt and acarrier.

Also provided is a method and composition for the topical treatment ofanorectal diseases that limits significant systemic effects and reducesthe occurrence of adverse events caused by the current approvedtherapies.

Also provided is a topical pharmaceutical gel composition for treatinganorectal diseases such as hemorrhoids, anal fissure (acute andchronic), painful conditions after anorectal surgery, perianal abscess,prolapsed thrombosed piles, perianal haematoma, cancer invading thesphincters (anorectal cancer), anal herpes, anal warts, anal itching,proctalgia fugax, constipation, anal bleeding and Crohn's disease oranother inflammatory bowel disease related anorectal disorders.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of at least one gelling agent;

about 0.001-5 w/w of at least one preservative;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of amlodipinebesylate comprising:

about 0.01-1% w/w of amlodipine besylate, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of hydroxyethyl cellulose;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of amlodipinebesylate comprising:

about 0.01-1% w/w of amlodipine besylate, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of at least one gelling agent;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of amlodipinebesylate comprising:

about 0.01-1% w/w of amlodipine besylate, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of hydroxyethyl cellulose;

about 0.01-5% w/w of methyl parahydroxybenzoate;

about 5-75% w/w of glycerin;

about 1-20 w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a method for the treatment of an anorectal diseasecomprising topically applying a topical pharmaceutical gel compositiondescribed herein to a skin surface of a patient in need thereof.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, all publications,patents, and patent applications mentioned in this specification areherein incorporated by reference to the same extent as if eachindividual publication, patent, or patent application was specificallyand individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings (also “Figure” and “FIG.” herein) of which:

FIG. 1 shows the mean±SD plasma level curves for amlodipine in femaleGottingen minipigs on day 28 when administered orally (Oral) ortopically as 0.2% topical pharmaceutical gel (Topical).

DESCRIPTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” or “some embodiments” or “a certain embodiment” means that aparticular feature, structure or characteristic described in connectionwith the embodiment is included in at least one embodiment. Thus, theappearances of the phrases “in one embodiment” or “in an embodiment” or“in some embodiments” or “in a certain embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Amlodipine is a dihydropyridine calcium antagonist that inhibits thetransmembrane influx of calcium ions into vascular smooth muscle andcardiac muscle. Experimental data suggest that amlodipine binds to bothdihydropyridine and nondihydropyridine binding sites. The contractileprocesses of cardiac muscle and vascular smooth muscle are dependentupon the movement of extracellular calcium ions into these cells throughspecific ion channels. Amlodipine inhibits calcium ion influx acrosscell membranes selectively, with a greater effect on vascular smoothmuscle cells than on cardiac muscle cells. Negative inotropic effectscan be detected in vitro but such effects have not been seen in intactanimals at therapeutic doses. Serum calcium concentration is notaffected by amlodipine. Within the physiologic pH range, amlodipine isan ionized compound (pKa=8.6), and its kinetic interaction with thecalcium channel receptor is characterized by a gradual rate ofassociation and dissociation with the receptor binding site, resultingin a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly onvascular smooth muscle to cause a reduction in peripheral vascularresistance and reduction in blood pressure.

Following administration of therapeutic doses to patients withhypertension, amlodipine produces vasodilation resulting in a reductionof supine and standing blood pressures. These decreases in bloodpressure are not accompanied by a significant change in heart rate orplasma catecholamine levels with chronic dosing. Although the acuteintravenous administration of amlodipine decreases arterial bloodpressure and increases heart rate in hemodynamic studies of patientswith chronic stable angina, chronic oral administration of amlodipine inclinical trials did not lead to clinically significant changes in heartrate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensiveeffectiveness is maintained for at least 24 hours. Plasma concentrationscorrelate with effect in both young and elderly patients. The magnitudeof reduction in blood pressure with amlodipine is also correlated withthe height of pretreatment elevation; thus, individuals with moderatehypertension (diastolic pressure 105-114 mmHg) had about a 50% greaterresponse than patients with mild hypertension (diastolic pressure 90-104mmHg). Normotensive subjects experienced no clinically significantchange in blood pressures (+1/−2 mmHg).

Amlodipine does not change sinoatrial nodal function or atrioventricularconduction in intact animals or man. In patients with chronic stableangina, intravenous administration of 10 mg did not significantly alterA-H and H-V conduction and sinus node recovery time after pacing.Similar results were obtained in patients receiving amlodipine andconcomitant beta-blockers. In clinical studies in which amlodipine wasadministered in combination with beta-blockers to patients with eitherhypertension or angina, no adverse effects on electrocardiographicparameters were observed. In clinical trials with angina patients alone,amlodipine therapy did not alter electrocardiographic intervals orproduce higher degrees of AV blocks.

After oral administration of therapeutic doses of amlodipine, absorptionproduces peak plasma concentrations between 6 and 12 hours. Absolutebioavailability has been estimated to be between 64 and 90%. Thebioavailability of amlodipine is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolitesvia hepatic metabolism with 10% of the parent compound and 60% of themetabolites excreted in the urine. Ex vivo studies have shown thatapproximately 93% of the circulating drug is bound to plasma proteins inhypertensive patients Elimination from the plasma is biphasic with aterminal elimination half-life of about 30-50 hours. Steady-state plasmalevels of amlodipine are reached after 7 to 8 days of consecutive dailydosing.

The pharmacokinetics of amlodipine are not significantly influenced byrenal impairment. Patients with renal failure may therefore receive theusual initial dose.

Elderly patients and patients with hepatic insufficiency have decreasedclearance of amlodipine with a resulting increase in AUC ofapproximately 40-60%, and a lower initial dose may be required. Asimilar increase in AUC was observed in patients with moderate to severeheart failure

Amlodipine is indicated for the treatment of hypertension to lower bloodpressure, symptomatic treatment of chronic stable angina, confirmed orsuspected vasospastic angina and to reduce the risk of hospitalizationfor angina and to reduce the risk of a coronary revascularizationprocedure.

The usual initial antihypertensive oral dose of Amlodipine is 5 mg oncedaily, and the maximum dose is 10 mg once daily. The recommended dosefor chronic stable or vasospastic angina is 5-10 mg, with the lower dosesuggested in the elderly and in patients with hepatic insufficiency.Most patients will require 10 mg for adequate effect. The effectiveantihypertensive oral dose in pediatric patients ages 6-17 years is 2.5mg to 5 mg once daily. Doses in excess of 5 mg daily have not beenstudied in pediatric patients.

As used herein, “amlodipine salt” refers to an acid addition salt ofamlodipine. Acid addition salts may be prepared by methods well known inthe art, and may be formed from organic and inorganic acids. Suitableacids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid(L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoricacid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid),caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconicacid (D), glucuronic acid (D), glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid,lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid(DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid,oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionicacid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid,toluenesulfonic acid (p), and undecylenic acid.

Also, as used in this specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontent clearly dictates otherwise.

As used herein, “amlodipine besylate” may be referred to as3-ethyl-5-methyl(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate,monobenzenesulphonate. Its empirical formula is C₂₀H₂₅ClN₂O₅.C₆H₆O₃S,and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecularweight of 567.1. It is slightly soluble in water and sparingly solublein ethanol. Amlodipine besylate tablets are formulated as white tabletsequivalent to 2.5, 5, and 10 mg of amlodipine for oral administration.In addition to the active ingredient, amlodipine besylate, each tabletcontains the following inactive ingredients: microcrystalline cellulose,dibasic calcium phosphate anhydrous, sodium starch glycolate, andmagnesium stearate. Amlodipine besylate is instable in aqueous solution.Various attempts were made in order to develop orally available liquidformulations (M. Friciu et.al. CJHP, 2016, 69(4), pp 327; I. KasagićVujanović, et.al., Contemporary Materials, 2014, V-2 (2014), pp 214; Z.{circumflex over (Z)}. Stoilkovi□et. al., Chem. Ind. Chem. Eng. Q.,2014, 20(2) pp 295; C. Milap et.al., Nahata, J Am Pharm Assoc., 1999,39, pp 375; A. Abdoh et.al., Pharm. Dev. Tecnol., 2004, 9(1), pp. 15),however stable liquid based formulations have not been developed todate.

There has been work done on the development of transdermal systems forcalcium channel antagonists (Zeng, et al., Drug Development andIndustrial Pharmacy, 2010, 36(6), pp 724; Y. Jiang, et al., Pharmazie,2008, 63, pp 356; Patel, et al., Asian Journal of Pharmaceutical andClinical Research, 2010, 3(1), pp 31). McDaid et.al. (InternationalJournal of Pharmaceutics, 1996, 133, pp 71) investigated the topicalabsorption of amlodipine besylate and confirmed that the compound wastoo hydrophilic for adequate transdermal delivery using a convenientarea of device, despite the use of penetration enhancers and increase inthe thermodynamic gradient across various rate-controlling membranes byethanol. Permeation of amlodipine from a range of hydrophilic andhydrophobic bases through hairless mouse skin was studied and theinfluence of the penetration enhancers, sodium lauryl sulphate 1% andpropylene glycol 20% in a sodium carboxymethylcellulose 3% gel base wasexamined. In vivo studies using rabbits were performed to assess thesuitability of a reservoir-type device. Employing data obtained from invitro studies involving human abdominal skin, it was possible to predictthe plasma profile resulting from the application of a similar deviceonto human skin over a period of 1 week and was found to be inadequatefor clinical use. No adverse local effects in the animal model arisingfrom the application of the transdermal device were observed. Thetherapeutic plasma level of amlodipine was in the range 3-10 ng/ml. Theaverage absorption rate of 1.24 μg/cm² per h would result in a dailydose of 0.59 mg amlodipine being delivered using an exposure area of 20cm². This dosage falls short of the desired level of ˜3.2 mg. Bothapplication sites in rabbits were examined visually for signs of localirritation after wearing the device for 3 days. No local irritation wasobserved at either application site, confirming that the device was welltolerated on dermal application even after several days of wear. Theseresults are not surprising as the Ca²⁺ antagonists inhibition activityin acute and chronic models of inflammation in a dose-dependent manneris widely known.

The subject invention is based on the discovery that anorectal diseasescan be treated by topical formulations comprising a calcium channelblocker, such as amlodipine salts. Moreover, this treatment can bedirected to the site of application and immediate surrounding areawithout a significant similar systemic effect.

Provided is a topical pharmaceutical gel composition comprising anamlodipine salt and a carrier.

In one aspect, the topical pharmaceutical gel compositions comprise anamlodipine salt and a carrier, with an amlodipine salt present at aconcentration chosen from about 1% w/w, about 0.5% w/w, about 0.2% w/w,about 0.1% w/w, about 0.05% w/w and 0.01% w/w, as measured as the freebase.

In an embodiment, the carrier comprises at least one glycol solvent, atleast one gelling agent, and at least one diluent.

In an embodiment, the carrier further comprises one or more componentschosen from preservatives and antioxidants.

In an embodiment, the carrier comprises one or more components chosenfrom hydroxyethyl cellulose, methyl parahydroxybenzoate, ethanol, water,propylene glycol, and glycerin.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of at least one gelling agent; and

about 0.001-5 w/w of at least one preservative.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of at least one gelling agent;

about 0.001-5% w/w of at least one preservative; and

at least one diluent.

In an embodiment, the amlodipine salt is chosen from amlodipinebesylate, amlodipine maleate, amlodipine mesylate, amlodipine adipate,amlodipine camsylate and amlodipine nicotinate. In an embodiment, theamlodipine salt is chosen from amlodipine besylate, amlodipine maleate,and amlodipine mesylate. In an embodiment, the amlodipine salt isamlodipine besylate.

In an embodiment, the amlodipine salt is present at a concentrationchosen from about 0.01% w/w to about 1% w/w, as measured as the freebase. In an embodiment, the amlodipine salt is present at aconcentration chosen from about 1% w/w, about 0.5% w/w, about 0.2% w/w,about 0.1% w/w, about 0.05% w/w and 0.01% w/w, as measured as the freebase.

In an embodiment, the at least one glycol solvent is chosen frompropylene glycol, polyethylene glycol, ethylene glycol, butylene glycol,hexalylene glycol, and mixtures thereof.

In an embodiment, the glycol solvent is polyethylene glycol.

In an embodiment, the at least one glycol solvent is present in anamount of about 5-75% w/w. In an embodiment, the at least one glycolsolvent is present in an amount of about 5-50% w/w. In an embodiment,the at least one glycol solvent is present in an amount of about 10-40%w/w. In an embodiment, the at least one glycol solvent is present in anamount of about 15-30% w/w, such as about 20-30% w/w, for example about25% w/w.

In an embodiment, the at least one gelling agent is chosen fromcarbomers, xanthan gum, acacia, tragacanth, sodium alginate, gelatin,modified starches, hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropyl methylcellulose, carboxymethyl cellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose phthalate, methylcellulose, co-polymers formed between maleic anhydride and methyl vinylether, methacrylate derivatives, polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, polyvinyl alcohol andmixtures thereof.

In an embodiment, the at least one gelling agent is chosen fromcarbomers, xanthan gum, acacia, tragacanth, sodium alginate, gelatin,modified starches, hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate,methyl cellulose, carboxymethyl cellulose, co-polymers formed betweenmaleic anhydride and methyl vinyl ether, methacrylate derivatives,polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers,polyvinyl alcohol and mixtures thereof.

In an embodiment, the gelling agent is hydroxyethyl cellulose.

In an embodiment, the at least one gelling agent is present in an amountof about 0.1-10% w/w. In an embodiment, the at least one gelling agentis present in an amount of about 0.1-5% w/w. In an embodiment, the atleast one gelling agent is present in an amount of about 1-% w/w. In anembodiment, the at least one gelling agent is present in an amount ofabout 1-4% w/w. In an embodiment, the at least one gelling agent ispresent in an amount of about 1, about 2, about 3, or about 4% w/w.

In an embodiment, the at least one preservative is chosen from methylparaben, propyl paraben, chlorocresol, thomersal, sorbic acid, potassiumsorbate, methyl parahydroxybenzoate and mixtures thereof.

In an embodiment, the preservative is methyl parahydroxybenzoate.

In an embodiment, the preservative is present in an amount of about0.001-5% w/w. In an embodiment, the preservative is present in an amountof about 0.001-1% w/w. In an embodiment, the preservative is present inan amount of about 0.001-0.005% w/w, such as about 0.001, about 0.002,about 0.003, about 0.004, or about 0.005% w/w.

In an embodiment, the topical pharmaceutical gel composition furthercomprises at least one diluent.

In an embodiment, the at least one diluent is chosen from ethanol,propanol, 2-propanol, water, glycerin, and mixtures thereof.

In an embodiment, the at least one diluent comprises about 5-75% w/w ofglycerin, such as about 5-70% w/w, about 5-65% w/w, about 5-60% w/w,about 5-55% w/w, about 5-50% w/w, about 5-45% % w/w, or about 4-40% w/w.

In an embodiment, the at least one diluent comprises about 1-20% w/w ofethanol, such as about 1-15% w/w or about 5-15% w/w, for example, about5, about 6, about 7, about 8, about 9, about 10, about 11, about 12,about 13, about 14, or about 15% w/w.

In an embodiment, the at least one diluent comprises about 10-40% w/w ofwater, such as about 10-35% w/w or 15-30% w/w, for example, about 15,about 16, about 17, about 18, about 19, about 20, about 21, about 22,about 23, about 24, about 25, about 26, about 27, about 28, about 29, orabout 30% w/w.

In an embodiment, the at least one diluent is a mixture of glycerin,ethanol, and water. In an embodiment, the at least one diluent is amixture of about 5-75% w/w of glycerin; about 1-20% w/w of ethanol; andabout 10-40% w/w of water. In an embodiment, the at least one diluent isa mixture of about 30-50% w/w of glycerin, about 5-15% w/w of ethanol,and about 15-35% w/w of water. In an embodiment, the at least onediluent is a mixture of about 20-30% w/w of glycerin, about 5-15% w/w ofethanol, and about 15-35% w/w of water. In an embodiment, the at leastone diluent is a mixture of about 40% w/w of glycerin, about 9-10% w/wof ethanol, and about 20-25% w/w of water.

In an embodiment, the topical gel composition further comprises a localanesthetic such as lidocaine or anti-inflammatory agent such as COX,COX-1 or COX-2 inhibitors or their mixtures.

In an embodiment, the topical gel composition further may comprise atleast one or more additional ingredients or excipients selected fromantioxidants, alkalizers or alkalizing agents, buffering agents,moisturizing agents, humectants, surfactants, neutralizing agents,chelating agents, and emollients. In an embodiment, the topical gelcomposition further may comprise at least one or more additionalingredients or excipients selected from buffering agents, moisturizingagents, humectants, surfactants, neutralizing agents, chelating agents,and emollients.

In an embodiment, the topical pharmaceutical gel composition furthercomprises at least one antioxidant. In an embodiment, the at least oneantioxidant is chosen from edetate disodium, sodium sulphite, sodiummetabisulfite, propyl gallate, edetate trisodium, tocopherolderivatives, butylated hydroxyl toluene, butylated hydroxyl anisole,ascorbic acid, fumaric acid, malic acid, citric acid, and mixturesthereof.

In an embodiment, the at least one antioxidant is present in an amountequal to or less than 5% w/w. In an embodiment, the pharmaceutical gelcomposition does not include at least one antioxidant.

In an embodiment, the topical pharmaceutical gel composition furthercomprises at least one alkalizer or alkanizing agent.

In an embodiment, the at least one alkalizer or alkanizing agent includeorganic and inorganic basic compounds. Examples of inorganic basic saltsinclude ammonium hydroxide, alkali metal salts, and alkaline earth metalsalts such as magnesium oxide, magnesium hydroxide, calcium hydroxide,sodium hydroxide, potassium hydroxide, lithium hydroxide, aluminumhydroxide, potassium carbonate, sodium bicarbonate and combinationsthereof.

In an embodiment, the alkalizer or alkanizing agent is aqueous sodiumhydroxide solution.

In an embodiment, the topical pharmaceutical gel compositions furthercomprise or are co-administered with steroids such as prednisolone,busenonide or hydrocortisone, anesthetics such as acetylsalicylic acid,locally acting lignocaine, and soothants.

In an embodiment, the topical pharmaceutical gel compositions furthercomprise typical components used in existing fissure or hemorrhoidaltreatment, such as zinc oxide, benzyl benzoate, bismuth oxide, bismuthsubgallate or Peru balsam.

In one aspect, the topical pharmaceutical gel composition comprises anamlodipine salt, hydroxyethyl cellulose, methyl parahydroxybenzoate,ethanol, water, propylene glycol, and glycerin with the amlodipine saltpresent at a concentration chosen from about 1 w/w, about 0.5% w/w,about 0.2% w/w, about 0.1% w/w, about 0.05% w/w and 0.01% w/w, asmeasured as the free base.

In one aspect, the topical pharmaceutical gel composition consistsessentially of amlodipine salt, hydroxyethyl cellulose, methylparahydroxybenzoate, ethanol, water, propylene glycol, and glycerin withthe amlodipine salt present at a concentration chosen from about 1% w/w,about 0.5% w/w, about 0.2% w/w, about 0.1% w/w, about 0.05% w/w and0.01% w/w, as measured as the free base.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of at least one gelling agent;

about 0.001-5% w/w of at least one preservative;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine besylate, as measured as the freebase;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of at least one gelling agent;

about 0.001-5% w/w of at least one preservative;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of at least one gelling agent;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of amlodipine besylate, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of at least one gelling agent;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of hydroxyethyl cellulose, carbomers, carboxymethylcellulose, or a mixture thereof;

about 0.01-5% w/w of methyl parahydroxybenzoate;

about 5-75% w/w of a glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine besylate, as measured as the freebase;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of hydroxyethyl cellulose, carbomers, carboxymethylcellulose, or a mixture thereof;

about 0.01-5% w/w of methyl parahydroxybenzoate;

about 5-75% w/w of a glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of an amlodipine salt, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of hydroxyethyl cellulose;

about 0.01-5% w/w of methyl parahydroxybenzoate;

about 5-75% w/w of a glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of amlodipine besylate, as measured as the free base;

about 5-75 w/w of propylene glycol;

about 0.1-10% w/w of hydroxyethyl cellulose;

about 0.01-5% w/w of methyl parahydroxybenzoate;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of amlodipine salt, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of hydroxyethyl cellulose;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

Also provided is a topical pharmaceutical gel composition of anamlodipine salt comprising:

about 0.01-1% w/w of amlodipine besylate, as measured as the free base;

about 5-75 w/w of at least one glycol solvent;

about 0.1-10% w/w of hydroxyethyl cellulose;

about 5-75% w/w of glycerin;

about 1-20% w/w of ethanol; and

about 10-40% w/w of water.

In an embodiment, the topical pharmaceutical gel formulation of anamlodipine salt is storage stable at room temperature for a period of atleast 24 months with 95-105% assay criterion limit.

In an embodiment, the topical pharmaceutical gel formulation of anamlodipine salt is storage stable at a temperature of 2-8° C. for aperiod of at least 24 months with 95-105% assay criterion limit.

In another aspect, degradation impurities (related substances) of anamlodipine salt in the topical pharmaceutical gel formulation is lessthan about 2.5% for a storage period of at least 24 months at roomtemperature.

In another aspect, degradation impurities (related substances) of anamlodipine salt in the topical pharmaceutical gel formulation is lessthan about 2.5% for a storage period of at least 24 months at atemperature of about 2-8° C.

In another aspect, relative bioavailability of topically appliedamlodipine salt in the topical pharmaceutical gel formulation is lessthan 10% compared to oral administration. The topical administration ofthe pharmaceutical gel formulation for 28 days resulted in no localtolerance of histopathological findings.

In an embodiment, the shear viscosity of the topical pharmaceutical gelcomposition is in the range of about 5 to 30 Pas measured at 10 s⁻¹shear rate by Kinexus Pro rheometer (Malvern Instruments Ltd.).

In an embodiment, the pH of the topical pharmaceutical gel compositionis in the range of about 4.0-8.0.

In an embodiment, the density of the topical pharmaceutical gelcomposition is in the range of about 0.9-1.5 g/ml.

In an embodiment, the topical pharmaceutical gel composition isformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, foam, oils, aerosols, suppositories orenemas.

In an embodiment, the topical pharmaceutical gel composition is appliedto the affected areas of the skin to a patient suffering from anorectaldiseases such as hemorrhoids, anal fissure and painful conditions afteranorectal surgery.

Disclosed herein are topical pharmaceutical gel compositions for use intreating anorectal diseases such as hemorrhoids, anal fissure (acute andchronic), painful conditions after anorectal surgery, perianal abscess,prolapsed thrombosed piles, perianal haematoma, cancer invading thesphincters (anorectal cancer), anal herpes, anal warts, anal itching,proctalgia fugax, constipation, anal bleeding and Crohn's disease oranother inflammatory bowel disease related anorectal disorders.

Also provided is a method for the treatment of an anorectal diseasecomprising topically applying a topical pharmaceutical gel compositionof any one of claims 1 to 15 to a skin surface of a patient in needthereof.

In an embodiment, the anorectal disease is chosen from hemorrhoids, analfissure (acute and chronic), painful conditions after anorectal surgery,perianal abscess, prolapsed thrombosed piles, perianal haematoma, cancerinvading the sphincters (anorectal cancer), anal herpes, anal warts,anal itching, proctalgia fugax, constipation, anal bleeding and Crohn'sdisease or another inflammatory bowel disease related anorectaldisorders.

Also disclosed herein is a method for the manufacture of topical gelformulation of an amlodipine salt. The method of manufacture comprisesthe following steps:

stirring the at least one diluent, the at least one glycol solvent, theamlodipine salt, the at least one preservative and the at least onegelling agent to form a gel; and

adding water up to the total weight/volume desired.

In an embodiment, the method of manufacture comprises the followingsteps:

mixing and homogenizing ethanol, glycol solvent and water;

dissolving an amlodipine salt and preservative in ethanol, glycolsolvent and water;

adding the gelling agent to the dissolved solution;

mixing and homogenizing the solution to obtain a gel;

adding glycerin to the gel under continuous stirring;

adding water up to the total weight/volume desired.

In an embodiment, the method for the manufacture of a topical gelformulation of an amlodipine salt comprises the following steps:

mixing and homogenizing ethanol, glycol solvent and water;

dissolving an amlodipine salt and methyl parahydroxybenzoate in ethanol,glycol solvent and water;

adding hydroxyethyl cellulose to the completely dissolved (b) solution;

mixing and homogenizing the solution to obtain a gel;

adding glycerin to the gel under continuous stirring;

adding water up to the total weight/volume desired.

The examples, which follow, are not intended to be limiting of the scopeof the present invention but read in conjunction with the detailed andgeneral description above, provide further understanding of the presentinvention and an outline of a process for preparing the compositions ofthe invention.

EXAMPLES Example 1 Preparation of Amlodipine Besylate TopicalPharmaceutical Gel Compositions Using Carbomer

Amlodipine besylate topical pharmaceutical gel compositions wereprepared using carbomer as gelling agent. Compositions of the preparedgels are summarized in Table 1.

TABLE 1 Topical pharmaceutical gel compositions prepared using carbomerSample No. #1 #2 #3 pH 7 6 5 Component Quantity (% w/w) Amlodipinebesylate 0.100-0.200 0.100-0.200 0.100-0.200 Carbomer (980 NF or 1.0001.010 0.950 971 or Ultrez 10) Ethanol 5.910 4.950 5.510-5.610 Methyl0.002 0.002 0.002 parahydroxybenzoate Glycerin 5.000 5.060 4.760 Sodiumhydroxide 0.410 0.270 0.120 Water 87.470-87.570 88.500-88.600 88.460 

Process of example #1: 0.2-0.4 g amlodipine besylate was dissolved in9.8 g ethanol. 87.8-87.6 g water was added to the solution and mixedwell. 2 g Carbomer was added to the prepared solution and stirred welluntil completely dissolved. Separately, 0.828 g sodium hydroxide wasdissolved in 107.2 g water and 2 mL 0.2% methyl parahydroxibenzoateethanolic solution was added. The two solutions were mixed together toform gel. 10 g glycerol was added to the gel and homogenized well.

Process of example #2: 0.2-0.4 g amlodipine-besylate was dissolved in9.8 g ethanol. 87.8-87.6 g water was added to the solution and mixedwell. 2 g Carbomer was added to the prepared solution and stirred welluntil completely dissolved. Separately, 0.540 g sodium hydroxide wasdissolved in 107.5 g water and 2 mL 0.2% methyl parahydroxibenzoateethanolic solution was added. The two solutions were mixed together toform gel. 10 g glycerol was added to the gel and homogenized well.

Process of example #3: 0.2 g Carbomer was dissolved in 100 g water. 0.25g sodium hydroxide was dissolved in 86 g water. The two solutions weremixed together to form gel. 2 mL 0.2% methyl parahydroxibenzoateethanolic solution, 10 g glycerol and 9.9-10 g 2-4% amlodipine-besylateethanolic solution were added to the gel and homogenized well.

Example 2 Preparation of Amlodipine Besylate Topical Pharmaceutical GelCompositions Using Carboxymethyl Cellulose

Amlodipine besylate topical pharmaceutical gel compositions wereprepared using carboxymethyl cellulose as gelling agent. Compositions ofthe prepared gels are summarized in Table 2.

TABLE 2 Topical pharmaceutical gel compositions prepared usingcarboxymethyl cellulose Sample No. #4 pH 7 Component Quantity (% w/w)Amlodipine besylate  0.100-0.200 Carboxymethyl cellulose 2.090 Ethanol6.150 Methyl parahydroxybenzoate 0.001 Glycerin 5.210 Water86.3400-86.440

Process of example #4: 0.1-0.2 g amlodipine-besylate was dissolved in4.9 g ethanol and then 5 g 0.2% methyl parahydroxibenzoate ethanolicsolution and 87.8-87.9 g water was added to the solution. 2 gcarboxymethyl cellulose was added to the solution to form a gel. 5 gglycerol was homogenized in the gel.

Example 3 Preparation of Amlodipine Besylate Topical Pharmaceutical GelCompositions Using Hydroxyethyl Cellulose

Amlodipine besylate topical pharmaceutical gel compositions wereprepared using hydroxyethyl cellulose as gelling agent. Compositions ofthe prepared gels are summarized in Table 3.

TABLE 3 Topical pharmaceutical gel compositions prepared usinghydroxyethyl cellulose Sample No. #5 #6 #7 pH 7 7 7 Component Quantity(% w/w) Amlodipine besylate 0.10-0.20 0.14-0.28 0.14-0.28 Hydroxyethylcellulose 2.00 2.00 2.00 Ethanol 5.91 10.86 9.60 Methyl 0.002 0.0020.100 parahydroxybenzoate Glycerin 5.00 40.00 40.00 Propylene glycol 0 025.00 Water 86.89-86.99 46.86-47.00 23.02-23.16

Process of example 5: 0.2-0.4 g amlodipine-besylate was dissolved in 9.8g ethanol and then 2 g 0.2% methyl parahydroxybenzoate ethanolicsolution and 173.6-173.8 g water was added to the solution. 4 ghydroxyethyl cellulose was added to the prepared solution and mixed wellto form a gel. 10 g glycerol was homogenized in the gel.

Process of example 6: 0.14-0.28 g amlodipine-besylate was dissolved in9.86 g ethanol and then 1 g 0.2% methyl parahydroxybenzoate ethanolicsolution and 46.95-47.00 g water was added to the solution. 2 ghydroxyethyl cellulose was added to the solution and mixed well to forma gel. 40 g glycerol was homogenized in the gel.

Process of example 7: 9.6 g ethanol, 25 g propylene glycol and23.02-23.16 g water was mixed well. 0.14-0.28 g amlodipine-besylate and0.1 g methyl parahydroxybenzoate was dissolved in the solvent mixture. 2g hydroxyethyl cellulose was added to the solvent mixture and mixed wellto form a gel. 40 g glycerol was homogenized in the gel.

Example 4 Preparation of Amlodipine Maleate and Amlodipine MesylateTopical Pharmaceutical Gel Compositions Using Hydroxyethyl Cellulose

Amlodipine maleate and amlodipine mesylate topical pharmaceutical gelcompositions were prepared using hydroxyethyl cellulose as gellingagent. Compositions of the prepared gels are summarized in Table 4.

TABLE 4 Topical pharmaceutical gel compositions prepared usinghydroxyethyl cellulose but different amlodipine salts, not amlodipinebesylate Sample No. #8 #9 pH 7 7 Component Quantity (% w/w) Amlodipinemaleate 0.13-0.26 0 Amlodipine mesylate 0 0.12-0.25 Hydroxyethylcellulose 2.00 2.00 Ethanol 9.60 9.60 Methyl parahydroxybenzoate 0.0040.004 Glycerin 40.00 40.00 Propylene glycol 25.00 25.00 Water23.14-23.27 23.15-23.27

Process of example 8: 9.6 g ethanol, 25 g propylene glycol and23.14-23.27 g water was mixed well. 0.13-0.26 g amlodipine-maleate and0.004 g methyl parahydroxybenzoate was dissolved in the solvent mixture.2 g hydroxyethyl cellulose was added to the solvent mixture and mixedwell to form a gel. 40 g glycerol was homogenized in the gel.

Process of example 9: 9.6 g ethanol, 25 g propylene glycol and23.15-23.27 g water was mixed well. 0.12-0,258 g amlodipine-mesylate and0.004 g methyl parahydroxybenzoate was dissolved in the solvent mixture.2 g hydroxyethyl cellulose was added to the solvent mixture and mixedwell to form a gel. 40 g glycerol was homogenized in the gel.

Example 5

Amlodipine besylate topical pharmaceutical gel compositions preparedaccording to Example 1-4 were stored in a closed vial at RT and 4° C. inorder to investigate the stability. At different time points relatedsubstances tests were performed by RP-HPLC method. Amlodipine besylatetopical pharmaceutical gel compositions prepared using hydroxyethylcellulose were more stable compared to the composition prepared usingcarbomer. Topical pharmaceutical gels of different amlodipine saltsprepared using hydroxyethyl cellulose showed different decompositionprofile after 1 month storage at 4° C. and RT. Only the amlodipinebesylate gel prepared using hydroxyethyl cellulose had satisfyingdegradation profile in both storage conditions. (Table 5).

TABLE 5 Amlodipine decomposition in different topical pharmaceutical gelcompositions in time. Amlodipine besylate content of sample #1-5 is0.1%. Amlodipine content of sample #6-9 is 0.1%. Degradation afterstorage at 4° C. Degradation after storage at RT (%) (%) Sample 1 2 1 23 1 2 1 2 3 No. week weeks month months months week weeks month monthsmonths #1 — — 0.50 — 1.18 — — 2.07 — 5.22 #2 — — 0.21 — 1.71 — — 1.85 —6.79 #3 0.53 — — — — 2.60 — — — — #4 — 0.14 — — — — 12.07 — — — #5 — —0.19 0.38 — — — 0.46 0.98 — #6 — — 0.24 — — — — 0.31 — — #7 — — 0.19 —0.32 — — 0.44 — 0.68 #8 — — 0.20 — — — — 0.93 — — #9 — — 0.28 — — — —0.33 — —

Example 6 In Vitro Permeability of Amlodipine Besylate TopicalPharmaceutical Gel Compositions

In vitro permeability of amlodipine besylate, amlodipine mesylate andamlodipine maleate gels was investigated using dialysis measurement. Thedonor compartment contained 4000 mg topical pharmaceutical gelcomposition, while the receiver medium was phosphate buffer, pH 7.4 (100ml). The measurement was performed at 37±0.5° C. The dialysis membranewas SnakeSkin Dialysis Tubing, 3.5K MWCO (35 mm dry I.D.). Amlodipinebesylate topical pharmaceutical gel composition prepared usinghydroxyethyl cellulose showed significantly higher in vitro permeabilitycompared to the compositions prepared with different amlodipine salts orusing carbomer as gelling agent. Amlodipine content of the receivercompartment was 1.7 times higher for the amlodipine besylate topicalpharmaceutical gel compositions prepared using hydroxyethyl cellulosecompared to other gels' (Table 6.).

TABLE 6 In vitro permeability of amlodipine besylate, amlodipinemesylate and amlodipine maleate gels Permeability of gel example #1Permeability of gel example #7 t Dissolved API in receiver Dissolved APIin receiver (min) compartment (%) compartment (%) 15 2.15 1.21 30 4.927.04 60 11.21 19.53 120 26.90 48.02 180 40.64 68.49 240 51.08 86.44Permeability of gel example #8 Permeability of gel example #9 tDissolved API in receiver Dissolved API in receiver (min) compartment(%) compartment (%) 15 0.77 0.54 30 3.25 2.75 60 10.19 9.35 120 29.2928.78 180 42.00 40.47 240 56.11 52.64

Example 7 28-Day Dermal Tolerance Study Followed by an 8-Day RecoveryPeriod in Minipigs Methods

The purpose of this study was to obtain information on the dermal localtolerance and dermal irritation of the 0.2% w/w amlodipine topicalpharmaceutical gel composition in minipigs administered twice dailytopically (dermal) over a period of 28 days and to assess reversibilityof any effect after an 8-day recovery period. In addition, thepharmacokinetic profile of the systemic exposure was investigated.

Amlodipine gel or placebo was measured onto plastic spatulas and washomogenously smeared on the left and right treatment sites (treatmentarea: approx. 20 cm²). The application sites were non-occluded.

Pharmacokinetic investigation: Approx. 3 mL blood was collected intoplastic vials containing K3-EDTA as anticoagulant at the following timepoints after last treatment: 0 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h,24 h, 36 h and 48 h after treatment (11 samples/animal). Amlodipine wasquantified in minipig plasma using a reliable LC-MS/MS method developedin ATRC. Deuterated analogue of amlodipine (Amlodipine-d4) served asinternal standard (IS). The plasma proteins were precipitated withmethanol and the supernatant subjected to reverse phase chromatographicseparation with gradient elution. Following electrospray ionization inpositive mode the analyte was detected in MRM mode at the followingtransitions: Amlodipine: 409.10→238.15 m/z, IS: 413.10→238.15 m/z,Calibration range: 50 pg/mL-50 ng/mL, LLOQ: 50 pg/mL. Pharmacokineticanalysis was performed using a validated Phoenix WinNonlin® softwareversion 6.3 (Pharsight Corporation, USA). The individual and mean plasmalevel versus time curves were evaluated using noncompartmental method.The results are shown in FIG. 1 and Table 7. It was be concluded that28-day repeated topical administration of 0.2% amlodipine gel resultedin very low total systemic exposure. At the end of the repeatedadministration all measured plasma concentrations remained below 300pg/mL and both the average C_(max) and AUC_(0-24 h) values were aroundthan 5% of those obtained after repeated oral administration at the samedose.

TABLE 7 Pharmacokinetic parameters following oral administration ofamlodipine tablets or topical administration of 0.2% topicalpharmaceutical gel in female Göttingen minipigs. Animal No. #1 #2 #3 #4Mean S.D. Oral, day 28, AUC 36.3495 46.079 62.522 55.6115 50.140511.4006 2 mg/day t_(max) 4.0 4.0 6.0 4.0 4.5 1 C_(max) 2.39 3.48 3.524.05 3.36 0.6969 Topical, day 28, AUC 0.918 3.9941 3.744 1.015 2.4177751.6794 2 mg/day t_(max) 36.0 0.0 4.0 4.0 4.0 16.7730 C_(max) 0.07650.265 0.276 0.0683 0.17145 0.1145

Viability, mortality and clinical signs: Viability, mortality andclinical signs were recorded three times daily (once before and twiceafter the first treatment) on the treatment days and twice on thetreatment-free days. No mortality occurred during the course of thestudy. No clinical signs were observed related to the amlodipine gelduring the study.

Body weight: Measurement of body weight was performed twice during theacclimatization period and then on the treatment days beforeadministration. There was no difference related to the test item in thebody weight gain between the animals treated with placebo and amlodipinegel.

Local tolerance: The treated skin area of the animals (on both side) wasobserved twice daily during treatment (before treatments) and recoveryperiods in order to evaluate the local tolerance with special regard toerythema, edema, inflammation, hypersensitivity, infection, biofilmformation, ischemia, necrosis, erysipelas and cellulitis. No localtolerance findings related to amlodipine gel or placebo were observed onthe treatment sites during the entire study

Necropsy: At the end of the recovery period (on study day 37). Noamlodipine gel or placebo related macroscopic findings were observed inany animals during necropsy.

Histopathology: Full histopathological examinations of samples fromtreatment sites from all animals. Treatment-related effects or toxicitywas not seen following 28 days dermal exposition and 8 days recoverywith placebo or amlodipine gel

In conclusion the dermal tolerance study with twice daily topical(dermal) amlodipine gel at dose level of 2 mg/animal/treatment tominipigs over a period of 28 days resulted in no adverse effects.According to the results, the 2 mg/animal/treatment dose was welltolerated in all animals.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

We claim:
 1. A method for treating an anorectal disease, comprisingtopically applying a topical pharmaceutical gel composition to a skinsurface of a patient in need thereof, wherein the topical pharmaceuticalgel composition comprises: about 0.01-1% w/w of an amlodipine salt, asmeasured as the free base; about 5-75% w/w of at least one glycolsolvent; about 0.1-10% w/w of at least one gelling agent; about 5-75%w/w of glycerin; about 1-20% w/w of ethanol; and about 10-40% w/w ofwater.
 2. The method of claim 1, wherein the topical pharmaceutical gelcomposition further comprises a local anesthetic.
 3. The method of claim2, wherein the local anesthetic is lidocaine.
 4. The method of claim 1,wherein the topical pharmaceutical gel composition further comprises ananti-inflammatory agent, wherein the anti-inflammatory agent is a COX-1or COX-2 inhibitor, or a mixture thereof.
 5. The method of claim 1,wherein the anorectal disease is selected from hemorrhoids, anal fissure(acute or chronic), painful conditions after anorectal surgery,prolapsed thrombosed piles, perianal haematoma, or proctalgia fugax. 6.The method of claim 1, wherein the anorectal disease is acute analfissure, and the topical pharmaceutical gel composition is topicallyapplied to an affected area of the skin.
 7. The method of claim 1,wherein the anorectal disease is chronic anal fissure, and the topicalpharmaceutical gel composition is topically applied to an affected areaof the skin.
 8. The method of claim 1, wherein the amlodipine salt isamlodipine besylate.
 9. The method of claim 1, wherein the topicalpharmaceutical gel composition further comprises at least onepreservative, wherein the at least one glycol solvent is propyleneglycol, wherein the at least one gelling agent is hydroxyethylcellulose. and wherein the at least one preservative is methylparahydroxybenzoate.
 10. The method of claim 1, wherein the amlodipinesalt is amlodipine besylate, wherein the ethanol is present in aconcentration of about 5-15% w/w, wherein the at least one gelling agentis hydroxyethyl cellulose, and wherein the water is present in aconcentration of about 15-35% w/w.
 11. The method of claim 1, whereinthe at least one gelling agent is hydroxyethyl cellulose.
 12. The methodof claim 1, wherein the amlodipine salt is present in in a dissolvedstate in the gel and is stable against degradation at a temperature of2-8° C. for a period of at least 24 months, as demonstrated by an assaylimit of between 95% and 105%.
 13. The method of claim 1, wherein theamlodipine salt is amlodipine besylate, and wherein the amlodipinebesylate is present in a dissolved state in the gel and is stableagainst degradation at a temperature of 2-8° C. for a period of at least24 months, as demonstrated by an assay limit of between 95% and 105%.14. The method of claim 1, wherein the degradation impurities of theamlodipine salt in the topical pharmaceutical gel composition is lessthan about 2.5% for a storage period of 24 months at room temperature.15. The method of claim 13, wherein the degradation impurities of theamlodipine besylate in the topical pharmaceutical gel composition isless than about 2.5% for a storage period of 24 months at a temperatureof about 2-8° C.
 16. The method of claim 1, wherein the amlodipine saltis amlodipine besylate, wherein the at least one glycol solvent ispropylene glycol, wherein the at least one gelling agent is hydroxyethylcellulose, wherein the topical pharmaceutical gel composition furthercomprises at least one preservative present in a concentration of about0.01-5% w/w, wherein the at least one preservative is methylparahydroxybenzoate, wherein the glycerin is present in a concentrationof about 30-50% w/w, wherein the ethanol is present in a concentrationof about 5-15% w/w, and wherein the water is present in a concentrationof about 15-35% w/w.
 17. The method of claim 1, wherein the topicalpharmaceutical gel composition has an active ingredient consistingessentially of the amlodipine salt.
 18. The method of claim 1, whereinthe amlodipine salt is present at a concentration of about 0.1-1% w/w,as measured as the free base.
 19. The method of claim 1, wherein thetopical pharmaceutical gel composition causes no erythema, edema,inflammation, hypersensitivity, infection, biofilm formation, ischemia,necrosis, erysipelas, cellulitis at the skin surface.
 20. The method ofclaim 1, wherein the anorectal disease is anal fissure, and wherein themethod treats pain associated with the anal fissure.